This application aims to study the application of functional magnetic resonance imaging in real time (rtfMRI) as an operant training feedback mechanism for treating substance use disorders. Recent data suggest that individuals can reduce activity in some brain regions (e.g. anterior cingulate cortex, anterior insula, auditory cortex when they are presented with information about activation in that brain region. Experimental and clinical pain have been reduced with rtfMRI signal feedback from the rostral anterior cingulate in a manner proportional to reductions in the blood oxygenation level dependent (BOLD) signal from that region. These regions overlap with those involved in the effects of substances of abuse and the development of substance use disorders (SUDs). The initial information opens the possibility of applying neurofeedback to improve treatment outcomes in patient samples. The present application seeks to expand the investigation of these processes and validate their applicability to substance dependent volunteers. In initial studies we will examine the capacity of nicotine dependent volunteers to reduce their craving for cigarettes. This substance was selected for its high retention rates and prevalence and public health burden in the general population, but it is expected that future studies would explore other forms of addiction (e.g. cocaine, opiates). Our multidisciplinary team proposes to advance current knowledge in this area by: (1) using data not from a single brain region, but from networks involved in nicotine craving and dependence, thereby accounting for inter- individual differences in brain regional activation patterns during nicotine craving;(2) developing a quantifiable method by using arterial spin labeling (ASL);and (3) determining the influence of individual expectations on these processes (e.g. assessing the degree to which these effects are attributable to placebo-related responding). The developmental and experimental elements of this application will lead to new avenues for treatment that would be readily generalizable to other forms of drug addiction besides nicotine, and potentially impacting on the outcomes of the substantial numbers of individuals seeking substance abuse treatment. PUBLIC HEALTH RELEVANCE: The development of new methodology for the treatment of patients with substance use disorders would represent a significant advance in the therapeutics of these disorders. The studies proposed offer a new treatment alternative for these otherwise highly recurrent and chronic illnesses.